Over 170 million people worldwide are infected by Hepatitis C virus. The current therapies have dose-limiting toxicity and there exists significant unmet medical need. Several compounds are under development that target HCV polymerase, HCV protease, and HCV NS5A. However, the viral replication cycle is significantly error-prone resulting in emergence of resistant mutants particularly under the selective pressure of antiviral therapy. This presents significant challenges to developing antiviral treatment regimes.
To date most anti-HCV agents that have been developed are HCV polymerase inhibitors. An NS3 protease inhibitor BILN-2061 was the first compound tested in humans that produced significant viral load reduction in patients. A nucleoside analog NM 283 showed antiviral effect in HCV-infected patients. However significant drug resistance and toxicity have been already noted with a few compounds in the clinic. Several antiviral compounds are under clinical development. For example, non-nucleoside benzothiadiazines, acyl pyrrolidines, benzofurans, phenylalanines, substituted thiophene, dihydropyranones, pyranoindoles, benzimidazoles and indole have been found to be inhibitors of NS5B polymerase domain. However, in vitro replicon assays reveal significant cross resistance with different drugs.
Because resistance development to antiviral drugs is virtually certain, one way to combat it has been combination treatments including drugs that may not promote cross-resistant mutants. Usually drugs that effect different viral enzymes do not show cross resistance and can be used in combinations successfully. Thus, a combination of different drugs with different mechanisms of action, which are not cross-resistant, will be the key to successful antiviral therapy.
Shorter chain oligonucleotides (less than 8-mers) with lesser number of charges and smaller molecular weight compared to 20-mer oligonucleotides represent a promising class of novel molecules with potential therapeutic properties as antivirals. Indeed, recent reports suggest that mono-, di-, tri-, and short chain oligonucleotides possess significant biological activity that can be exploited for various therapeutic applications. However, improved short oligonucleotides having improved properties for oral, transdermal or other non-invasive modes of delivery to the patient are still needed for use as stand alone therapeutics or in combination therapies.